The proposed project will investigate the influence of thyroid hormone status on the regulation of hepatic carbohydrate metabolism by insulin, glucagon, catecholamines, vasopressin and angiotensin. Emphasis will be placed on defining the effects of both hyperthyroidism and hypothyroidism on the hormonal regulation of glycogenolysis in isolated rat liver parenchymal cells. The ability of the glycogenolytic hormones epinephrine, glucagon, vasopressin and angiotensin and the ability of the anti-glycogenolytic hormone insulin to regulate glucose output, cyclic AMP levels, activation of protein kinase, and activation of glycogen phosphorylase will be measured in isolated hepatocytes from rats of altered thyroid states. We have demonstrated that hypothyroidism enhances beta-adrenergic activation of glycogen phosphorylase activity and intracellular cyclic AMP accumulation in isolated rat hepatocytes. We plan to seek identification of the component(s) of the beta-adrenergic hormone/adenylate cyclase complex responsible for this increased sensitivity and capacity to respond to beta-adrenergic agonists. Adenylate cyclase activity, cyclic AMP phosphodiesterase activity, and both alpha-adrenergic and beta-adrenergic hormone receptors will be assayed in whole homogenates and in plasma membranes prepared from these hepatocytes. We will assess the effects of both hyperthyroidism and hypothyroidism on the ability of insulin to regulate glycogen synthase activity in isolated rat hepatocytes. Emphasis will be placed on defining the role of thyroid hormones in modulating insulin action with respect to control of hepatic glycogen metabolism. The proposed project is designed to investigate the biochemical mechanism(s) involved in this modulation of hormonally-regulated hepatic carbohydrate metabolism by thyroid status.